The present invention relates to new bis-platinum complexes in which two platinum cores are connected by a polymethylene derivative ligand and to pharmaceutical compositions containing them.
The use of platinum complexes in cancer chemotherapy is well known. Cisplatin (CDDP) for example is used in therapy to treat testicular, ovarian, head and neck and small cell lung carcinomas. However, treatment with cisplatin may result in severe nephrotoxicity. A further clinical disadvantage is the problem of aquired drug resistance resulting in the tumor becoming refractory to treatment by the agent.
To overcome the nephrotoxic effects of cisplatin, a second-generation analogue, carboplatin, was developed. Carboplatin, or [Pt(NH3)2(CBDCA)] (where CBDCA stands for 1,1-cyclobutanedicarboxylate), is clinically effective against the same spectrum of carcinomas as cisplatin, but exhibits a reduction in the nephrotoxic effects.
A number of different mono- and bis-platinum complexes have been prepared in an attempt to treat different tumors or carcinomas (U.S. Pat. Nos. 4,225,529; 4,250,189; 4,553,502; 4,565,884). None of such compounds is currently used in therapy.
More recently, new bis-platinum(II) complexes are disclosed (U.S. Pat. No. 4,797,393), which have a bridging diamine or polyamine ligand and primary or secondary amines or pyridine type nitrogen-carrying ligands attached to the platinum complex, as well as two different or identical monoanionic ligands which may be a halide, phosphate, nitrate, carboxylate, substituted carboxylate or one dianionic ligand such as sulfate or dicarboxylate. The expert technician will appreciate that the complex is neutral, since two anions counter-balance the +2 charge on each platinum core.
WO 91/03482 further discloses bis-platinum(II) complexes such as those described in U.S. Pat. No. 4,797,393, the main difference consisting in having two nitrogen-carrying neutral ligands and only one simple charged ligand on each platinum core. This results in a complex having a +2 total charge. These complexes interfere with DNA replication forming interstrand cross-links, which cause conformational changes on the DNA and eventually lead to the inhibition of replication and to the final cytotoxic effect.
Even if such compounds are able to partially overcome the resistance to cisplatin in cisplatin-resistant cell lines and thus may have a broader spectrum of activity than cisplatin, nevertheless their activity against the non-resistant lines appears lower when compared with cisplatin (see Table I).
On the other hand, polyamines are considered essential in cell proliferation. The naturally occurring polyamines in mammalian cells are putrescine, spermidine and spermine. A wide variety of related amines are found in other organisms and may play critical roles in their physiology. Nevertheless, it is also known that the association of cationic polyamines with negatively charged DNA induces significant structural changes in DNA. Spermidine and spermine can cause DNA to condense and aggregate and induce B-to-Z transition in certain DNA sequences (Marton, L. J. et al., Annu. Rev. Pharmacol. Toxicol., 1995, 35: 55-91). This led the researchers to focus their attention on the potential use of polyamines as antitumor drugs (Basu, H. S. et al., Biochem. J., 1990, 269: 329-334; Yanlong Li et al., J. Med. Chem., 1996, 39: 339-341).
We have now found that modifying the polyamine chain by replacing the secondary nitrogens with different basic and not basic groups brings to bis-platinum complexes with a particularly interesting activity as antitumor agents.
Bis-platinum complexes bridged by ligands that carry two amide functionalities were disclosed in Inorg. Chem., 34, 2316-22 (1994), but in those compounds two amine groups chelate each platinum atom, which results in a different conformational behaviour with respect to the complexes of the present invention. Moreover, they bring two leaving ligands (chloride or dimethylsulphoxide) on each platinum core, therefore the total charge and the reactivity too are expected to be different.